A5086634691- Blood properties and coagulation
- Platelet Disorders and Treatments
- Helicobacter pylori-related gastroenterology studies
- Venous Thromboembolism Diagnosis and Management
- Gastric Cancer Management and Outcomes
- Erythrocyte Function and Pathophysiology
- Cancer-related gene regulation
- Antiplatelet Therapy and Cardiovascular Diseases
- TGF-β signaling in diseases
- Protease and Inhibitor Mechanisms
- Galectins and Cancer Biology
- Cancer Cells and Metastasis
- Acute Ischemic Stroke Management
- Blood Coagulation and Thrombosis Mechanisms
- Cancer Research and Treatments
- Heparin-Induced Thrombocytopenia and Thrombosis
- Metabolism, Diabetes, and Cancer
- Digestive system and related health
- Skin and Cellular Biology Research
- Bone and Dental Protein Studies
- Coronary Interventions and Diagnostics
- Diabetic Foot Ulcer Assessment and Management
- Neonatal Respiratory Health Research
- Acute Myocardial Infarction Research
- Neurological Disorders and Treatments
University of Leeds
2015-2025
University Hospital Leipzig
2023
University of Sheffield
2016
St James's University Hospital
2010-2013
University of Liverpool
2005-2012
Physiological Society
2010
Hemostasis requires conversion of fibrinogen to fibrin fibers that generate a characteristic network, interact with blood cells, and initiate tissue repair. The network is porous highly permeable, but the spatial arrangement external clot face unknown. Here we show transitioned blood-air interface through Langmuir film formation, producing protective confining clots in human mouse models. We demonstrated only required for formation film, it occurred vitro vivo. connected underlying tethering...
Summary Factor XIII is responsible for the cross-linking of fibrin γ-chains in early stages clot formation, whilst α-chain occurs at a slower rate. Although γ- and was previously shown to contribute stiffness, role both chains determining structure currently unknown. Therefore, aim this study determine individual α- γ-chain during its effects on structure. We made use recombinant fibrinogen (γQ398N/Q399N/K406R), which does not allow y-chain cross-linking. In absence cross-linking, intact D-D...
BackgroundThe glycoprotein VI (GPVI) signaling pathway was previously reported to direct procoagulant platelet activity through collagen binding. However, the impact of GPVI-fibrin interaction on development and how it modulates clot structure are unknown.ObjectivesTo determine effect phenotype its structure.MethodsProcoagulant platelets in platelet-rich plasma clots were determined by scanning electron microscopy (wild-type GPVI-deficient murine samples) confocal microscopy. Procoagulant...
Matrix metalloproteinase-7 (MMP-7) is localized to epithelial cells and up-regulated in many cancers inflammation. We now report that MMP-7 targets a key mesenchymal cell type, the myofibroblast. Recombinant stimulated proliferation migration of human colonic myofibroblasts. These responses were partly attributable activation other MMPs, notably MMP-3 MMP-8, stimulation mitogen-activated protein kinase phosphatidylinositol 3-kinase signaling pathways. Using proteomic approach, we identified...
GPVI (glycoprotein VI) is a key molecular player in collagen-induced platelet signaling and aggregation. Recent evidence indicates that it also plays important role aggregation thrombus growth through interaction with fibrin(ogen). However, there are discrepancies the literature regarding whether monomeric or dimeric form of binds to fibrinogen at high affinity. The mechanisms not clear, including which region responsible for binding. We aimed gain further understanding level identify...
Tumor progression has been linked to changes in the stromal environment. Myofibroblasts are cells that often increased tumors but their contribution cancer is not well understood. Here, we show secretomes of myofibroblasts derived from gastric cancers [cancer-associated (CAMs)] differ a functionally significant manner those adjacent tissue [adjacent (ATMs)]. CAMs showed rates migration and proliferation compared with ATMs or normal (NTMs). Moreover, conditioned medium (CM) significantly...
Factor XIII (FXIII) cross-links fibrin upon activation by thrombin. Activation involves cleavage at residue 37 thrombin, releasing an peptide. A common polymorphism (valine to leucine variant 34, V34L), located in the peptide, has been associated with increased rates and paradoxically a protective effect cardiovascular disease. There is, currently, no data available on effects of V34L from vivo models thrombosis. We examined FXIII clot formation cross-linking vivo.We generated panel...
Essentials Venous thromboembolism (VTE) recurrence leads to decreased clot elastic modulus in plasma. Recurrent VTE is not linked changes structure, fiber radius, or factor XIII activity. Other plasma components may play a role recurrence. Prospective studies should resolve if stiffness can be used as predictor for recurrent VTE. SUMMARY: Background associated with high risk of events after withdrawal anticoagulation. Objectives To determine the difference mechanical properties between...
Background: Thromboinflammation of adipose tissue involves accumulation pro-fibrinogenic factors to in obesity, which promotes immune cell infiltration, affects weight gain and can lead metabolic dysfunction. The role neutrophil genes inflammation are frequently investigated using MRP8-Cre mice generate neutrophil-specific knockouts. Recent study demonstrated that have off-target deletions Serpine1 Ap1s1 genes. Serpine1, encoding plasminogen activator inhibitor-1, is a key anti-fibrinolytic...
Platelet activation is constrained by endothelial-derived prostacyclin (PGI2) through cyclic adenosine-5'-monophosphate (cAMP) signalling involving multiple isoforms of adenylyl cyclase (AC). The roles specific AC in controlling haemostasis remain unclear and require clarification. To understand the contribution AC6 platelet haemostatic thrombotic function. A platelet-specific knockout (AC6-KO) mouse was generated. Biochemical approaches were used to determine intracellular signalling, with...
Coronary artery disease (CAD) plaque rupture leads to occlusive thrombosis, causing acute myocardial infarction requiring immediate life-saving treatment. The blood clot is supported by a mesh of fibrin fibres that are generated through the polymerisation fibrin. We recently showed also produces film on surface clots. Our aim was study if occurs intravascularly thrombi from patients with infarction. In this observational study, we recruited 42 ST-elevation (STEMI) and obtained intra-coronary...
Fibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) composed an αC-domain and αC-connector. Two recombinant variants (α390 α220) were produced to investigate role subregions in modulating clot stability resistance lysis. α390 variant, truncated before αC-domain, clots with a denser structure thinner fibres. In contrast, α220 at start αC-connector, that porous short, stunted fibres visible fibre ends. These mechanically weak susceptible Our data...
The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide. Current treatment options are based on anticoagulation, which is suboptimal for preventing further embolic events. In order to develop better treatments we sought understand the structural and mechanical properties blood clots how this influences embolism in vivo. We developed murine model fibrin γ-chain cross-linking by activated...
The gastric pathogen Helicobacter pylori (H. pylori) is linked to peptic ulcer and cancer, but the relevant pathophysiological mechanisms are unclear. We now report that H. stimulates expression of plasminogen activator inhibitor (PAI)-1, urokinase (uPA), its receptor (uPAR) in epithelial cells consequences for cell proliferation. Real-time PCR biopsies from corpus, not antrum, showed significantly increased PAI-1, uPA, uPAR pylori-positive patients. Transfection primary human with or...
Plasminogen activator inhibitor (PAI)-1 is associated with cancer progression, fibrosis and thrombosis. It expressed in the stomach but mechanisms controlling its expression there, biological role, are uncertain. We sought to define role of gastrin regulating PAI-1 determine relevance for gastrin-stimulated cell migration invasion. In gastric biopsies from subjects elevated plasma gastrin, abundances PAI-1, urokinase plasminogen (uPA), uPA receptor (uPAR) mRNAs measured by quantitative PCR...
Fibrin polymerization, following fibrinopeptides A and B (FpA, FpB) cleavage, relies on newly exposed α- β-chains N-termini (GPR, GHR; A-, B-knobs, respectively) engaging preexistent a b pockets in other fibrin(ogen) molecules' γ- (B)β-chains C-terminal regions. role for mostly disordered (A)α-chains regions "bridging" between fibrin molecules/fibrils has been proposed.Fibrinogen Detroit is clinically observed mutation (AαR19 → S) with nonengaging GPS A-knobs. By analogy, similar Bβ-chain...